Pruritus (itch sensation) is a symptom derived from many nervous system disorders that afflicts a large population of humans and is treated by a variety of pharmacological agents with variable success. Little effort has been made to develop valid animal models of itch for preclinical evaluation of potential antipruritics. Recent studies illustrate distinct species differences in the in vivo pharmacology of itch, which may contribute to different results or interpretations in itch research. Humans and monkeys have similar thresholds for detecting stimuli and the neural systems responsible for sensations in both species are fundamentally similar. Therefore, it is important to conduct studies using unanesthetized monkeys to validate animal behavioral models and to assess the effectiveness of potential antipruritics. In particular, previous studies have demonstrated that intrathecally administered morphine-induced scratching behavior in monkeys is mediated by central mu opioid receptors. Using pharmacological approaches, we intend to establish other experimental itch models using different pruritogenic agents and to determine the effectiveness of kappa opioid receptor agonists as antipruritics in a broader context in behaving monkeys. The proposed studies in this project will test the central hypothesis that activation of kappa opioid receptors attenuates itch evoked by a variety of pruritogenic agents in primates. In the proposed studies, scratching activity will be monitored by video recorders and quantified by observers blind to experimental conditions. The potential attenuation of scratching activity by rationally selected pharmacological agents will be studied in different experimental itch models. The dose- response curve, time course of each agent, and possible side effects will be thoroughly investigated. Collectively, these studies will develop valid animal models of itch, improve scientific knowledge of itch in primates, and advance the discovery of innovative therapies targeting the kappa opioid receptors for the treatment of pruritus in humans. PUBLIC HEALTH RELEVANCE: Itch/Pruritus is a symptom of many clinical disorders and drug treatments that afflicts a large population of humans. However, little research has been made to improve our understanding of the receptor mechanisms of itch and potential antipruritics. The purpose of this application is to establish more experimental itch models in primates and to determine and compare the effectiveness of different drugs as potential antipruritics in a broader context. If proposed aims are achieved, it will facilitate the development of antipruritics and reduce the medical and financial burdens of itch in a global community.